Biological therapies, such as aldesleukin (IL-2), for metastatic renal cell carcinoma (mRCC) are designed to mobilize immune effector cells that recognize and destroy cancer. IL-2 induces durable complete remissions (CR) but only in a minority of patients. We have recently observed a 50% objective response rate (16% CR) in mRCC patients treated with autologous tumor lysate-dendritic cell (DC)-vaccine, IL-2 and interferon (IFNa). New agents inhibiting vascular endothelial growth factor (VEGF) pathways have demonstrated significant benefit in mRCC patients as well, but rarely induce CRs. High blood VEGF is associated with poor response to IL-2 and can cause tumor specific immune dysregulation. Blocking VEGF pathways has been demonstrated to impede regulatory/inhibitory T cells and re-establish immune competency. To test whether complementary mechanisms of immune activation and disruption of regulatory pathways enhance outcome we plan to treat 24 mRCC patients in a redesigned phase II trial using bevacizumab, DC vaccine, IL-2, and IFNa. Observations from this project will be used in the development of novel cancer therapies which, if successful, will decrease the burden of cancer on the public. DCs initiate cellular and humoral immune responses but are dysfunctional in the presence of VEGF. IL- 2 induces T-cell activation and proliferation and reverses acquired T-cell defects. IFNa enhances tumor immunogenicity through expression of MHC molecules and tumor associated antigens, and can enhance DC and T-cell function. VEGF blockade can inhibit regulatory cells and restore function to DCs. Bevacizumab, an FDA approved anti-VEGF antibody with activity in mRCC, is safe to administer with IL-2 or IFNa. RCC removed as standard care will be processed for autologous vaccine. Eligible and consented patients with mRCC will undergo leukaphereses to obtain peripheral blood monocyte derived DCs. Bevacizumab will be administered prior to ultrasound guided lymph node injections of DCs loaded with autologous tumor lysate and followed by IL-2 + IFNa therapy. We propose to determine 1) the objective clinical response rate to treatment and progression free survival, 2) the clinical and autoimmune related toxicity profile of therapy, and 3) the treatment related tumor-specific immune response and the relationship of tumor-specific immune response and objective clinical response. PUBLIC HEALTH RELEVANCE: Our novel therapeutic approach will provide proof of principle that regulation of both inflammatory and inhibitory immune pathways using combination therapy (bevacizumab, DCs + IL-2/IFNa) can overcome immune resistance and enhance clinical activity. Observations from this project will be used in the development of new and original cancer therapies which, if successful, will decrease the burden of cancer on the public.